Abstract
SUMMARY The multisubstrate/multifunctional proline-directed protein kinase FA (PDPK FA) was found to be highly expressed in tumor mass, even more highly expressed in invasive lesion and preferentially overexpressed in highly metastatic spread area of the resected cancerous tissue sections obtained from pancreatic ductal adenocarcinoma patients, suggesting an association of dynamic overexpression of this signal transducing molecule with the progression of the highly malignant phenotypes of pancreatic cancer. The molecular, cellular and animal studies using the antisense-suppression strategic design further demonstrate this point. In comparisons with the parental and control-transfected clones, the selected and characterized antisense stably-transfected clones of human pancreatic ductal adenocarcinoma cells (MIA PaCa-2) with the specific suppression of overexpressed PDPK FA, as demonstrated by immunoblot and immunocytochemical analysis, exhibited malignant growth retardation, diminished tumorigenesis, loss of invasive/highly metastatic spread potentials including ascites formation and splenomegaly in SCID mice, and enhancement of chemoradiosensitivities. The clinicopathologic study further revealed that the randomly-recruited 35 pancreatic ductal adenocarcinoma patients expired within one year even after complete medications all exhibited invasive/metastatic PDPK FA expression in their resected cancerous tissue sections, in sharp contrast to the well-established, clinically-used CA 199 marker which could detect only less than 70% of the patients under identical conditions. All the results obtained from molecular, cellular, animal and clinicopathologic studies presented in this thesis taken together demonstrate PDPK FA as a newly-described, previously-undiscovered signal transducing molecule essential for the development of highly malignant phenotypes of pancreatic cancer. The present thesis establishes PDPK FA as a novel potential target for diagnosis, disease monitoring, drug screening and new therapeutic strategies to improve the extremely poor survival rate of pancreatic ductal adenocarcinoma patients.